Plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer
INTRODUCTION
Almost two thirds of patients with muscle-invasive bladder cancer (MIBC) undergoing cystectomy after cisplatin-based neoadjuvant chemotherapy (NAC) have invasive disease. Biological alterations of these cisplatin-resistant tumors induced by NAC remain largely unstudied.
METHODS
Radical cystectomy (RC) samples were available for gene expression analysis from 133 patients treated with cisplatin-based NAC who had residual invasive disease, of whom 116 had matched pre-NAC samples. In addition, the tumor bed (non-neoplastic scar tissue) of 21 post-NAC RC specimens with complete pathologic response (i.e. pT0N0) was profiled. Unsupervised consensus clustering was performed and the clusters were investigated for their biological and clinical characteristics. H&E staining and immunohistochemistry (IHC) on tissue microarrays were used to confirm tissue sampling and the gene expression analysis.
RESULTS
Unsupervised consensus clustering yielded four distinct consensus clusters (CC) or subtypes: CC1-Basal, CC2-Luminal, CC3-Immune and CC4-Scar-like. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal-like (KRT5/6, KRT14) and a luminal-like (GATA3, PPARG) phenotype, respectively. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecules (CTLA4, CD80). Finally, the CC4-Scar-like profile was consistent with non-neoplastic scar samples, expressing genes associated with wound healing / scarring (MYH11, SHH, CNN1). Approximately the same numbers of pre-NAC basal- and luminal-like samples remained static (CC1 or CC2) with respect to subtype or were highly immune-infiltrated (CC3) in the post-NAC setting. In the post-NAC setting, luminal-like pre-NAC samples were more likely adopt a scar-like character (CC4).
CONCLUSION
This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.
Funding: GenomeDx performed gene expression analysis